Genetic Variant NM_006265.3:c.1162-7_1162-6dupTT (chr8-116852713-T-TAA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_006265.3(RAD21):c.1162-7_1162-6dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,167,612 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 0 hom. )

Consequence

RAD21
NM_006265.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.189

Publications

3 publications found

Variant links:

Genes affected

RAD21 (HGNC:9811): (RAD21 cohesin complex component) The protein encoded by this gene is highly similar to the gene product of Schizosaccharomyces pombe rad21, a gene involved in the repair of DNA double-strand breaks, as well as in chromatid cohesion during mitosis. This protein is a nuclear phospho-protein, which becomes hyperphosphorylated in cell cycle M phase. The highly regulated association of this protein with mitotic chromatin specifically at the centromere region suggests its role in sister chromatid cohesion in mitotic cells. [provided by RefSeq, Jul 2008]

RAD21 Gene-Disease associations (from GenCC):

Cornelia de Lange syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Cornelia de Lange syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Mungan syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

RAD21 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00102 (138/135358) while in subpopulation AMR AF = 0.00267 (36/13492). AF 95% confidence interval is 0.00198. There are 0 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 138 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD21	NM_006265.3 link	c.1162-7_1162-6dupTT		splice_region_variant, intron_variant	Intron 9 of 13	ENST00000297338.7	NP_006256.1	O60216A0A024R9J0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD21	ENST00000297338.7 link	c.1162-7_1162-6dupTT		splice_region_variant, intron_variant	Intron 9 of 13	1	NM_006265.3	ENSP00000297338.2		O60216

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

138

AN:

135316

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000431

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00267

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000938

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.000534

GnomAD2 exomes

AF:

0.00170

AC:

148

AN:

87152

AF XY:

0.00165

show subpopulations

Gnomad AFR exome

AF:

0.00151

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00201

Gnomad EAS exome

AF:

0.00126

Gnomad FIN exome

AF:

0.000936

Gnomad NFE exome

AF:

0.00160

Gnomad OTH exome

AF:

0.00121

GnomAD4 exome

AF:

0.00213

AC:

2202

AN:

1032254

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1059

AN XY:

507726

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00344

AC:

AN:

22108

American (AMR)

AF:

0.00195

AC:

AN:

19014

Ashkenazi Jewish (ASJ)

AF:

0.000717

AC:

AN:

16734

East Asian (EAS)

AF:

0.000587

AC:

AN:

27248

South Asian (SAS)

AF:

0.00365

AC:

158

AN:

43328

European-Finnish (FIN)

AF:

0.000823

AC:

AN:

36442

Middle Eastern (MID)

AF:

0.000769

AC:

AN:

3900

European-Non Finnish (NFE)

AF:

0.00216

AC:

1775

AN:

821328

Other (OTH)

AF:

0.00225

AC:

AN:

42152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.311

Heterozygous variant carriers

175

350

525

700

875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00102

AC:

138

AN:

135358

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

65278

show subpopulations

African (AFR)

AF:

0.000431

AC:

AN:

37162

American (AMR)

AF:

0.00267

AC:

AN:

13492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3238

East Asian (EAS)

AF:

0.00

AC:

AN:

4714

South Asian (SAS)

AF:

0.000942

AC:

AN:

4248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

61942

Other (OTH)

AF:

0.000530

AC:

AN:

1886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000330

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.19

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over